Endogenous steroidal androgen such as testosterone or 5α-dihydrotestosterone (DHT) exerts physiological and pathophysiological actions by binding to an androgen receptor (referred to as “AR”), a nuclear receptor. AR induces cell strain-specific gene expression in a target tissue. AR consists of three main functional domains including a ligand binding domain (LBD), a DNA binding domain and an amino terminal domain. A substance which binds to AR and shows an endogenous steroidal androgenic action is called AR agonist, while the one which inhibits the action of AR ligand is called AR antagonist. After AR binds to a ligand and the product is delivered into a nucleus, the product forms a complex with plural proteins such as a transcription coupling factor and a cell strain-specific coupling factor and binds to a target gene or an androgen responsive element (ARE), which is a DNA sequence (binding motif) in the region of a promoter or enhancer of genes that AR easily binds to, and thereby controls the production of protein encoded by a specific gene.
Androgen has actions such as a protein anabolic action, a gonadotropin secretion inhibitory action, and the promoting action of erythropoiesis as well as that in the reproductive system, and target cells for androgen are variously distributed into organs including external sex organs, accessory sex organs as well as brain, pituitary gland, muscle tissues, bones, and kidneys (NPL 1). The androgenic protein anabolic action includes the increase of a skeletal muscle mass and skeletal muscular strength, and the increase of bone quantity and bone density (NPL 2). Therefore, androgen is expected to be useful for prevention and/or treatment for disuse muscle atrophy occurring as a result of inactivity by sarcopenia and bedridden or immobilization resulting from plaster cast fixation, cachexia (such as cancers, heart failure, chronic obstructive pulmonary disease and end-stage renal disease and the like), furthermore, muscular dystrophy (such as Duchenne dystrophy, myotonic dystrophy and the like).
However, steroidal androgen has a poor first-pass effect in the liver, and hepatotoxicity and cross reactivity with other steroid hormone receptors such as glucocorticoid receptor (GR) have become problem (NPL 1). Therefore, a selective androgen receptor modifier (SARM) as nonsteroidal androgen, which increases a skeletal muscle mass, muscular strength, bone quantity and bone density by binding to AR, is highly promising by selective binding to AR compared to other steroid hormone receptors without danger of hepatotoxicity. Therefore, many SARMs are under development in an early development stage (NPL 3). Ostelin (brand name) has the most developed and its phase I and phase II clinical trials have been completed (NPL 4). In addition, SARM is expected to be effective for the use in the promotion of regeneration and restoration of muscles (NPL 5), in the area of hormonal male contraception and benign prostatic hypertrophy (BPH) and wound healing (NPL 6).
In PTL's 1-5, a compound is disclosed whose partial structure is coincident with the amino azole derivative of the present invention. However, the same compound is not described and there is no description about their relations to AR. A compound with the activity of AR antagonist is described in NPL 7, but its chemical structure is different from the amino azole derivative of the present invention. Further, NPL 7 does not suggest that the amino azole derivative of the present invention has an AR agonist activity.